Angelw: the first case of enantioselective dearomatization of 3-nitroindole catalyzed by phosphine

The catalytic asymmetric dearomatization (cadA) can transform two-dimensional planar aromatics into three-dimensional complex molecular structures, which provides a practical and effective synthesis method for the construction of chiral rings in natural products and bioactive molecules Compared with the electronic rich heteroaromatics, the electronic deficient heteroaromatics are still the challenging substrates for the asymmetric cadA reactions Therefore, the development of an effective catalytic system for asymmetric cadA reactions has always been the pursuit of chemists Recently, nitroindole has been proved to be a good substrate for various dearomatization and enantioselectivity reactions, including palladium catalyzed cycloaddition, Lewis acid catalyzed cyclization and thiocarbamate or thiourea promoted cyclization Recently, Professor Lu Yixin and colleagues from National University of Singapore reported the enantioselective [3 + 2] cyclization of nitroindole and diene mediated by chiral phosphine This reaction can be used for the enantioselective construction of a variety of cyclopentadiene alkaloid skeletons, and it is also the first example of phosphorus catalyzed cyclization for the dearylation reaction Relevant research results were published in angelw.chem Int ed (DOI: 10.1002/anie.201900248) Firstly, the conditions of catalyst and solvent were screened with nitroindole (1) and benzyl 2,3-dienoate (2) as model substrates The results show that the catalysts P1 and P4 containing sulfonamide and thiourea will lead to low yield, the catalysts P2 and P3 containing carbamate or amide group have good catalytic effect, while the dipeptide phosphine catalyst p6-p9 has ideal catalytic effect When P8 was used as catalyst, 92% yield and 96% ee of the product could be obtained The results showed that toluene was the best solvent (source: angelw Chem Int ed.) next, the author evaluated the substrate range (scheme 2) of this dearylation reaction All kinds of 3-nitroindole and different ester substituted enoate can react smoothly, and the corresponding target product can be obtained with excellent yield and EE value Halogen, nitro group, ester and cyano group are compatible with reaction conditions The absolute configuration of 3N was confirmed by X-ray crystal structure analysis In addition, ethyl 2-butyrate can also be used in the dearylation reaction (eq.1) Although the yield of the reaction is low, it still has excellent enantioselectivity (source: angelw Chem Int ed.) based on the literature reports, the author proposed the possible mechanism of the reaction (scheme 3) In order to further understand the process of dearylamization, two kinds of indoles with different electrical properties were used for the intermolecular competition experiment (eq.2) The reaction rate of electron deficient substrate 1K is faster than that of electron rich substrate 1E, which indicates that the addition of 2,3-double bond of zwitterionic intermediate a to indole is the decisive step in the whole process of dearylation (source: angelw Chem Int ed.) (source: angelw Chem Int ed.) Then, the correlation between the aromaticity of 3-nitroindole and the rate of dearylation was studied A series of 3-nitroindoles with different N-protecting groups were synthesized and then dearylated (scheme 4) The results showed that the protective group of carbamate was the most effective, and the electron absorbing n-protective groups such as toluene sulfonyl (TS) and benzoyl (BZ) could reduce the reaction rate greatly (source: angelw Chem Int ed.) the de aromatization step is very important to the kinetics of the reaction In addition, the aromaticity of indole determines the formation of the product DFT results show that ASE is related to the yield These results indicate that the ring dearylation may be the main challenge of the reaction (source: angelw Chem Int ed.) finally, we studied the derivatization of the products 3a and 3b (scheme 5) The reduction of nitro group by Zn / tmscl is easy to convert to chiral product 4 The α, β - unsaturated esters of 3B can be partially hydrogenated to obtain 4B The cracking of BOC Group and the reduction of ester lead to the formation of alcohol 4C The dihydroxylation of the double bond is easy to occur, and the corresponding chiral diol is obtained for 4 days (source: angelw Chem Int ed.) conclusion: Professor Lu Yixin and his colleagues from National University of Singapore have achieved high enantioselective dearomatization of 3-nitroindole by phosphine catalyzed [3 + 2] cyclization This reaction represents the first example of the application of phosphine mediated cyclization to dearylation.